A comprehensive review on the role of co-signaling receptors and Treg homeostasis in autoimmunity and tumor immunity.
A comprehensive review on the role of co-signaling receptors and Treg homeostasis in autoimmunity and tumor immunity.
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DOI：
10.1016/j.jaut.2018.08.007
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发表时间：
2018-12
影响因子：
12.8
通讯作者：
Prabhakar BS
中科院分区：
文献类型：
--
作者：
Kumar P;Bhattacharya P;Prabhakar BS
免疫系统确保针对入侵微生物和肿瘤抗原产生最佳的 T 效应器 (Teff) 免疫反应，同时在调节性 T (Treg) 细胞的帮助下防止针对自身抗原的不当自身免疫反应。因此，Treg 和 Teff 细胞通过相互调节帮助维持免疫稳态。虽然Tregs可以通过抑制抗肿瘤Teff反应来促进肿瘤免疫逃避，但Tregs功能的丧失可能导致Teff针对自身抗原产生反应，从而导致自身免疫性疾病。因此，Teff/Treg 细胞之间稳态平衡的丧失通常与癌症和自身免疫相关。共刺激和共抑制受体统称为共信号受体，在 Teff 和 Treg 细胞扩增和功能的调节中发挥着不可或缺的作用，因此在调节自身免疫和抗肿瘤免疫反应中发挥着关键作用。在过去的三十年中，人们为了解协同信号受体的生物学及其在免疫稳态中的作用付出了巨大的努力。 CTLA4 和 PD1 等共抑制受体的突变与小鼠和人类的 Treg 功能障碍以及自身免疫性疾病有关。另一方面，生长中的肿瘤通过 CTLA4、PD1 和 PDL-1 的表达利用共抑制信号传导来逃避免疫监视。使用抗 CTLA4 和抗 PD1 的免疫检查点阻断 (ICB) 引起了人们对肿瘤免疫学中协同信号受体的极大关注，并引起了人们对研究其他协同信号受体的新兴趣，而这些受体直到最近才得到充分研究。除了共抑制受体外，共刺激受体如 OX40、GITR 和 4-1BB 也广泛参与免疫稳态和 T 细胞刺激，并且使用针对 OX40、GITR 和 4-1BB 的激动性抗体可有效引起肿瘤消退。尽管 ICB 在癌症治疗中取得了前所未有的成功，但 ICB 由于 Treg 稳态丧失而引起的自身免疫不良事件构成了主要障碍。在此，我们全面综述了各种共刺激和共抑制受体在Treg生物学和免疫稳态、自身免疫和抗肿瘤免疫中的作用。此外，我们讨论了针对这些共同信号受体以增强抗肿瘤免疫反应而产生的自身免疫不良事件。
The immune system ensures optimum T-effector (Teff) immune responses against invading microbes and tumor antigens while preventing inappropriate autoimmune responses against self-antigens with the help of T-regulatory (Treg) cells. Thus, Treg and Teff cells help maintain immune homeostasis through mutual regulation. While Tregs can contribute to tumor immune evasion by suppressing anti-tumor Teff response, loss of Treg function can result in Teff responses against self-antigens leading to autoimmune disease. Thus, loss of homeostatic balance between Teff/Treg cells is often associated with both cancer and autoimmunity. Co-stimulatory and co-inhibitory receptors, collectively known as co-signaling receptors, play an indispensable role in the regulation of Teff and Treg cell expansion and function and thus play critical roles in modulating autoimmune and anti-tumor immune responses. Over the past three decades, considerable efforts have been made to understand the biology of co-signaling receptors and their role in immune homeostasis. Mutations in co-inhibitory receptors such as CTLA4 and PD1 are associated with Treg dysfunction, and autoimmune diseases in mice and humans. On the other hand, growing tumors evade immune surveillance by exploiting co-inhibitory signaling through expression of CTLA4, PD1 and PDL-1. Immune checkpoint blockade (ICB) using anti-CTLA4 and anti-PD1 has drawn considerable attention towards co-signaling receptors in tumor immunology and created renewed interest in studying other co-signaling receptors, which until recently have not been as well studied. In addition to co-inhibitory receptors, co-stimulatory receptors like OX40, GITR and 4-1BB have also been widely implicated in immune homeostasis and T-cell stimulation, and use of agonistic antibodies against OX40, GITR and 4-1BB has been effective in causing tumor regression. Although ICB has seen unprecedented success in cancer treatment, autoimmune adverse events arising from ICB due to loss of Treg homeostasis poses a major obstacle. Herein, we comprehensively review the role of various costimulatory and co-inhibitory receptors in Treg biology and immune homeostasis, autoimmunity, and anti-tumor immunity. Furthermore, we discuss the autoimmune adverse events arising upon targeting these co-signaling receptors to augment anti-tumor immune responses.
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影响因子：
4.4
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